1. Field of the Invention
The present invention relates to a novel method of increasing the aqueous solubility and bioavailability of the platinum antitumor complex, bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV), having the structural formula ##STR1## which will also be referred to below and in the claims by its literature codename, JM216. The invention also provides novel suppository dosage forms of JM216 adapted for rectal administration.
2. Description of the Prior Art
JM216 is an antitumor platinum (IV) complex presently undergoing clinical evaluation as an oral antitumor agent. The complex is described in U.S. Pat. Nos. 5,244,919 and 5,072,011.
Although the oral dosage form of JM216 being pursued in the clinic has obvious advantages over injectable platinum complexes such as cisplatin and carboplatin, it is reported by M. J. McKeage et al in Cancer Chemother. Pharmacol. 36: 451-458 (1995) that the current oral capsule form may have certain pharmacokinetic disadvantages. In a phase I clinical study C.sub.max and AUC increased less than proportionally to dose at dose levels .gtoreq.200 mg/m.sup.2. This was associated with greater interpatient pharmacokinetic variation and reduced urinary platinum recovery. Such pharmacokinetic variation and reduced gastro-intestinal drug absorption may be due to the poor water-solubility of JM216 which the present inventors have determined to be 0.3 mg/ml at 23.degree. C.
In addition to the bioavailability problems, there are important reasons why it is often preferred to administer a drug like JM216 rectally rather than orally, e.g. nausea, vomitting and stomach irritation associated with oral dosing, inability to swallow and the possibility of partly avoiding the hapatic first pass clearance.